2-Deoxyfortimicin A is a novel aminoglycoside antibiotic disclosed in commonly assigned U.S. patent application Ser. No. 863,006, filed Dec. 21, 1977. The antibiotic has the following structure: ##STR1##
2-Deoxyfortimicin A has in vitro anti-bacterial activity equal to that of fortimicin A, but enhanced in vivo activity against certain bacteria such as Klebsiella pneumoniae and Proteus mirabilis. Furthermore, 2-deoxyfortimicin A could not be inactivated by R-factor carrying microorganisms which might modify the 2-hydroxyl group of the parent fortimicins.
Production of 2-deoxyfortimicin A heretofore has required a lengthly process which resulted in only a 25-30% yield of the antibiotic. The method involved producing 2-deoxyfortimicin A from fortimicin B, having all primary amino groups protected by benzyloxycarbonyl groups and the C.sub.5 hydroxyl and C.sub.4 secondary amino group blocked by a suitable aldehyde to form an oxazolidine ring, which, upon treatment with a hydrocarbonsulfonyl halide or anhydride, is converted to a 2-O-hydrocarbonsulfonyl ester, such as a 2-O-methanesulfonyl ester.
The ester in turn is converted to a 1,2',6'-tri-N-benzyloxycarbonyl-2-O-hydrocarbonsulfonyl ester derivative, which, following acid hydrolysis of the oxazolidine ring, is N-deblocked by catalytic hydrogenolysis in the presence of an acid. When the resulting 2-O-hydrocarbonsulfonylfortimicin B salt is converted to the free base, the intermediate, 1,2-epiminofortimicin B is obtained. Continuing the process, catalytic hydrogenolysis of 1,2-epiminofortimicin B gives 2-deoxyfortimicin B which in turn is converted to the 1,2',6'-tri-N-benzyloxycarbonyl intermediate by treatment with a suitable acylating agent such as N-(benzyloxycarbonyloxy)succinimide. The tri-N-benzyloxycarbonyl intermediate is acylated with an activated carboxylic acid derivative to obtain a per-N-blocked 2-deoxy-4-N-acylfortimicin B derivative which is converted to tetra-N-benzyloxy-2-deoxyfortimicin A by reacting the fortimicin B intermediate with an active ester such as the N-hydroxysuccinimide ester of N-benzyloxycarbonylglycine in the presence of tetrahydrofuran. Chromatography yields the per-N-blocked intermediate which is converted to 2-deoxyfortimicin A as the tetrahydrochloride salt by hydrogenolysis in methanolic hydrogen chloride in the presence of 5% palladium on carbon.
The yield generally obtained from the above-described procedure is about 25-30 percent and requires separation of 2-deoxyfortimicin A from a co-produced end product. There has been a need for a simpler, more economical, higher yield processes for producing this valuable antibiotic. The present invention provides such a process which requires fewer steps and results in a 50-60 percent yield of 2-deoxyfortimicin A.